Sandimmune

"Potential drug treatments are tested on paper, in laboratories and eventually
in thousands of people. But every drug that goes through this cycle â€“ every drug
that FDA approves â€“ carries some risk. One of the first lines of defense against
"...

SIDE EFFECTS

Hypertension

Hypertension, which is usually mild to moderate, may
occur in approximately 50% of patients following renal transplantation and in
most cardiac transplant patients.

Glomerular Capillary Thrombosis

Glomerular capillary thrombosis has been found in
patients treated with cyclosporine and may progress to graft failure. The
pathologic changes resemble those seen in the hemolytic-uremic syndrome and
include thrombosis of the renal microvasculature, with platelet-fibrin thrombi
occluding glomerular capillaries and afferent arterioles, microangiopathic
hemolytic anemia, thrombocytopenia, and decreased renal function. Similar
findings have been observed when other immunosuppressives have been employed
posttransplantation.

Hypomagnesemia

Hypomagnesemia has been reported in some, but not all,
patients exhibiting convulsions while on cyclosporine therapy. Although
magnesium-depletion studies in normal subjects suggest that hypomagnesemia is
associated with neurologic disorders, multiple factors, including hypertension,
high-dose methylprednisolone, hypocholesterolemia, and nephrotoxicity
associated with high plasma concentrations of cyclosporine appear to be related
to the neurological manifestations of cyclosporine toxicity.

Clinical Studies

The following reactions occurred in 3% or greater of 892
patients involved in clinical trials of kidney, heart, and liver transplants:

Sandimmune® (cyclosporine)
was discontinued on a temporary basis and then restarted in 18 additional
patients.

Patients receiving immunosuppressive
therapies, including cyclosporine and cyclosporine -containing regimens, are at
increased risk of infections (viral, bacterial, fungal, parasitic). Both
generalized and localized infections can occur. Pre-existing infections may
also be aggravated. Fatal outcomes have been reported. (See WARNINGS)

Infectious Complications in the Randomized Renal
Transplant Patients

Complication

Sandimmune® Treatment
(N=227)
% of Complications

Standard Treatment*
(N=228)
% of Complications

Septicemia

5.3

4.8

Abscesses

4.4

5.3

Systemic Fungal Infection

2.2

3.9

Local Fungal Infection

7.5

9.6

Cytomegalovirus

4.8

12.3

Other Viral Infections

15.9

18.4

Urinary Tract Infections

21.1

20.2

Wound and Skin Infections

7.0

10.1

Pneumonia

6.2

9.2

*Some patients also received ALG.

Cremophor® EL
(polyoxyethylated castor oil) is known to cause hyperlipemia and
electrophoretic abnormalities of lipoproteins. These effects are reversible
upon discontinuation of treatment but are usually not a reason to stop
treatment.

Headache, including Migraine

Cases of migraine have been
reported. In some cases, patients have been unable to continue cyclosporine,
however, the final decision on treatment discontinuation should be made by the
treating physician following the careful assessment of benefits versus risks.

DRUG INTERACTIONS

Effect of Drugs and Other Agents on Cyclosporine
Pharmacokinetics and/or Safety

All of the individual drugs cited below are well
substantiated to interact with cyclosporine. In addition, concomitant use of
nonsteroidal anti-inflammatory drugs with cyclosporine, particularly in the
setting of dehydration, may potentiate renal dysfunction. Caution should be
exercised when using other drugs which are known to impair renal function. (See
WARNINGS, Nephrotoxicity)

Drugs That May Potentiate Renal Dysfunction

Antibiotics

Antineoplastic

Antifungals

Anti- Inflammatory Drugs

Gastrointestinal Agents

Immunosuppressives

Other Drugs

ciprofloxacin

melphalan

amphotericin B

azapropazon

cimetidine

tacrolimus

fibric acid derivatives (e.g., bezafibrate, fenofibrate)

gentamicin tobramycin trimethoprim with sulfamethoxazole

ketoconazole

colchicine diclofenac naproxen

ranitidine

methotrexate

vancomycin

sulindac

During the concomitant use of a
drug that may exhibit additive or synergistic renal impairment potential with
cyclosporine, close monitoring of renal function (in particular serum
creatinine) should be performed. If a significant impairment of renal function
occurs, reduction in the dosage of cyclosporine and/or co-administered drug or
an alternative treatment should be considered.

Cyclosporine is extensively
metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of
the multidrug efflux transporter P-glycoprotein. Various agents are known to
either increase or decrease plasma or whole blood concentrations of
cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein
transporter or both. Compounds that decrease cyclosporine absorption such as
orlistat should be avoided. Appropriate Sandimmune® (cyclosporine)
dosage adjustment to achieve the desired cyclosporine concentrations is
essential when drugs that significantly alter cyclosporine concentrations are
used concomitantly. (See Blood Concentration Monitoring.)

HIV Protease inhibitors

The HIV protease inhibitors
(e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit
cytochrome P-450 3A and thus could potentially increase the concentrations of
cyclosporine, however no formal studies of the interaction are available. Care
should be exercised when these drugs are administered concomitantly.

Bosentan

Co-administration of bosentan
(250 - 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg
every 12 hours for 2 days then dosing to achieve a Cmin of 200-250 ng/mL) for 7
days in healthy subjects resulted in decreases in the cyclosporine mean
dose-normalized AUC, Cmax, and trough concentration of approximately 50%, 30%
and 60%, respectively, compared to when cyclosporine was given alone. (See also
Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs
or Agents)

Boceprevir

Co-administration of boceprevir
(800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in
healthy subjects resulted in increases in the mean AUC and Cmax of cyclosporine
approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine
was given alone.

Telaprevir

Co-administration of telaprevir
(750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in
healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax
of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to
when cyclosporine (100 mg single dose) was given alone.

St John's Wort

There have been reports of a
serious drug interaction between cyclosporine and the herbal dietary
supplement, St. John's Wort. This interaction has been reported to produce a
marked reduction in the blood concentrations of cyclosporine, resulting in
subtherapeutic levels, rejection of transplanted organs, and graft loss.

Rifabutin

Rifabutin is known to increase
the metabolism of other drugs metabolized by the cytochrome P-450 system. The
interaction between rifabutin and cyclosporine has not been studied. Care
should be exercised when these two drugs are administered concomitantly.

Effect of Cyclosporine on the
Pharmacokinetics and/or Safety of Other Drugs or Agents

Cyclosporine is an inhibitor of
CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase
plasma concentrations of comedications that are substrates of CYP3A4 or
P-glycoprotein or both.

Cyclosporine may reduce the
clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors
(statins) and aliskiren, repaglinide, NSAIDs, sirolimus, etoposide, and other
drugs. See the full prescribing information of the other drug for further
information and specific recommendations. The decision on co-administration of
cyclosporine with other drugs or agents should be made by the physician following
the careful assessment of benefits and risks.

Digoxin

Severe digitalis toxicity has
been seen within days of starting cyclosporine in several patients taking
digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin
concentrations should be monitored.

Colchicine

There are reports on the
potential of cyclosporine to enhance the toxic effects of colchicine such as
myopathy and neuropathy, especially in patients with renal dysfunction.
Concomitant administration of cyclosporine and colchicine results in
significant increases in colchicine plasma concentrations. If colchicine is
used concurrently with cyclosporine, a reduction in the dosage of colchicine is
recommended.

HMG Co-A reductase inhibitors
(statins)

Literature and postmarketing
cases of myotoxicity, including muscle pain and weakness, myositis, and
rhabdomyolysis, have been reported with concomitant administration of
cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and
rarely, fluvastatin. When concurrently administered with cyclosporine, the
dosage of these statins should be reduced according to label recommendations.
Statin therapy needs to be temporarily withheld or discontinued in patients
with signs and symptoms of myopathy or those with risk factors predisposing to
severe renal injury, including renal failure, secondary to rhabdomyolysis.

Repaglinide

Cyclosporine may increase the
plasma concentrations of repaglinide and thereby increase the risk of
hypoglycemia. In 12 healthy male subjects who received two doses of 100mg
cyclosporine capsule orally 12 hours apart with a single dose of 0.25mg
repaglinide tablet (one half of a 0.5mg tablet) orally 13 hours after the
cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8
fold (range: 0.6 - 3.7 fold) and 2.4 fold (range 1.2 - 5.3 fold), respectively.
Close monitoring of blood glucose level is advisable for a patient taking
cyclosporine and repaglinide concomitantly.

Anthracycline antibiotics

High doses of cyclosporine
(e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure
to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in
cancer patients.

Aliskiren

Cyclosporine alters the
pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14
healthy subjects who received concomitantly single doses of cyclosporine (200
mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was
increased by approximately 2.5 fold (90% CI: 1.96 - 3.17) and the mean AUC by
approximately 4.3 fold (90% CI: 3.52 - 5.21), compared to when these subjects
received aliskiren alone. The concomitant administration of aliskiren with
cyclosporine prolonged the median aliskiren elimination half-life (26 hours
versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The
mean AUC and Cmax of cyclosporine were comparable to reported literature
values. Co-administration of cyclosporine and aliskiren in these subjects also
resulted in an increase in the number and/or intensity of adverse events,
mainly headache, hot flush, nausea, vomiting, and somnolence. The
co-administration of cyclosporine with aliskiren is not recommended.

Bosentan

In healthy subjects,
co-administration of bosentan and cyclosporine resulted in mean increases in
dose-normalized bosentan trough concentrations on day 1 and day 8 of
approximately 21-fold and 2fold , respectively, compared to when bosentan was
given alone as a single dose on day 1. (See also Effect of Drugs and Other
Agents on Cyclosporine Pharmacokinetics and/or Safety)

Potassium sparing diuretics

Cyclosporine should not be used
with potassium-sparing diuretics because hyperkalemia can occur. Caution is also
required when cyclosporine is coadministered with potassium-sparing drugs
(e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor
antagonists), potassium-containing drugs as well as in patients on a
potassium-rich diet. Control of potassium levels in these situations is
advisable.

Nonsteroidal Anti-inflammatory
Drug (NSAID) Interactions

Clinical status and serum
creatinine should be closely monitored when cyclosporine is used with
nonsteroidal anti-inflammatory agents in rheumatoid arthritis patients. (See WARNINGS)

Pharmacodynamic interactions
have been reported to occur between cyclosporine and both naproxen and
sulindac, in that concomitant use is associated with additive decreases in
renal function, as determined by 99mTc-diethylenetriaminepentaacetic
acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant
administration of diclofenac does not affect blood concentrations of cyclosporine,
it has been associated with approximate doubling of diclofenac blood levels and
occasional reports of reversible decreases in renal function. Consequently, the
dose of diclofenac should be in the lower end of the therapeutic range.

Methotrexate Interaction

Preliminary data indicate that
when methotrexate and cyclosporine were coadministered to rheumatoid arthritis
patients (N=20), methotrexate concentrations (AUCs) were increased
approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy
methotrexate, were decreased by approximately 80%. The clinical significance of
this interaction is not known. Cyclosporine concentrations do not appear to
have been altered (N=6).

Sirolimus

Elevations in serum creatinine
were observed in studies using sirolimus in combination with full-dose
cyclosporine. This effect is often reversible with cyclosporine dose reduction.
Simultaneous coadministration of cyclosporine significantly increases blood
levels of sirolimus. To minimize increases in sirolimus blood concentrations,
it is recommended that sirolimus be given 4 hours after cyclosporine
administration.

Nifedipine

Frequent gingival hyperplasia
when nifedipine is given concurrently with cyclosporine has been reported. The
concomitant use of nifedipine should be avoided in patients in whom gingival
hyperplasia develops as a side effect of cyclosporine.

Methylprednisolone

Convulsions when high dose
methylprednisolone is given concomitantly with cyclosporine have been reported.